SKI controls MDS-associated chronic TGF-{beta} signaling, aberrant splicing, and stem cell fitness

Publication Date:
2018-11-23
Publisher:
American Society of Hematology (ASH)
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
Medicine
Keywords:
Myeloid Neoplasia, e-Blood
Published by:
http://www.hematology.org/
_version_ 1836399091197673473
autor Muench, D. E., Ferchen, K., Velu, C. S., Pradhan, K., Chetal, K., Chen, X., Weirauch, M. T., Colmenares, C., Verma, A., Salomonis, N., Grimes, H. L.
beschreibung The transforming growth factor beta (TGF-β) signaling pathway controls hematopoietic stem cell (HSC) behavior in the marrow niche; however, TGF-β signaling becomes chronic in early-stage myelodysplastic syndrome (MDS). Although TGF-β signaling normally induces negative feedback, in early-stage MDS, high levels of microRNA-21 (miR-21) contribute to chronic TGF-β signaling. We found that a TGF-β signal–correlated gene signature is sufficient to identify an MDS patient population with abnormal RNA splicing (eg, CSF3R ) independent of splicing factor mutations and coincident with low HNRNPK activity. Levels of SKI messenger RNA (mRNA) encoding a TGF-β antagonist are sufficient to identify these patients. However, MDS patients with high SKI mRNA and chronic TGF-β signaling lack SKI protein because of miR-21 activity. To determine the impact of SKI loss, we examined murine Ski –/– HSC function. First, competitive HSC transplants revealed a profound defect in stem cell fitness (competitive disadvantage) but not specification, homing, or multilineage production. Aged recipients of Ski –/– HSCs exhibited mild phenotypes similar to phenotypes in those with macrocytic anemia. Second, blastocyst complementation revealed a dramatic block in Ski –/– hematopoiesis in the absence of transplantation. Similar to SKI- high MDS patient samples, Ski –/– HSCs strikingly upregulated TGF-β signaling and deregulated expression of spliceosome genes (including Hnrnpk ). Moreover, novel single-cell splicing analyses demonstrated that Ski –/– HSCs and high levels of SKI expression in MDS patient samples share abnormal alternative splicing of common genes (including those that encode splicing factors). We conclude that miR-21–mediated loss of SKI activates TGF-β signaling and alternative splicing to impair the competitive advantage of normal HSCs (fitness), which could contribute to selection of early-stage MDS-genic clones.
citation_standardnr 6360033
datenlieferant ipn_articles
feed_id 310
feed_publisher American Society of Hematology (ASH)
feed_publisher_url http://www.hematology.org/
insertion_date 2018-11-23
journaleissn 1528-0020
journalissn 0006-4971
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher American Society of Hematology (ASH)
quelle Blood
relation http://www.bloodjournal.org/cgi/content/short/132/21/e24?rss=1
schlagwort Myeloid Neoplasia, e-Blood
search_space articles
shingle_author_1 Muench, D. E., Ferchen, K., Velu, C. S., Pradhan, K., Chetal, K., Chen, X., Weirauch, M. T., Colmenares, C., Verma, A., Salomonis, N., Grimes, H. L.
shingle_author_2 Muench, D. E., Ferchen, K., Velu, C. S., Pradhan, K., Chetal, K., Chen, X., Weirauch, M. T., Colmenares, C., Verma, A., Salomonis, N., Grimes, H. L.
shingle_author_3 Muench, D. E., Ferchen, K., Velu, C. S., Pradhan, K., Chetal, K., Chen, X., Weirauch, M. T., Colmenares, C., Verma, A., Salomonis, N., Grimes, H. L.
shingle_author_4 Muench, D. E., Ferchen, K., Velu, C. S., Pradhan, K., Chetal, K., Chen, X., Weirauch, M. T., Colmenares, C., Verma, A., Salomonis, N., Grimes, H. L.
shingle_catch_all_1 SKI controls MDS-associated chronic TGF-{beta} signaling, aberrant splicing, and stem cell fitness
Myeloid Neoplasia, e-Blood
The transforming growth factor beta (TGF-β) signaling pathway controls hematopoietic stem cell (HSC) behavior in the marrow niche; however, TGF-β signaling becomes chronic in early-stage myelodysplastic syndrome (MDS). Although TGF-β signaling normally induces negative feedback, in early-stage MDS, high levels of microRNA-21 (miR-21) contribute to chronic TGF-β signaling. We found that a TGF-β signal–correlated gene signature is sufficient to identify an MDS patient population with abnormal RNA splicing (eg, CSF3R ) independent of splicing factor mutations and coincident with low HNRNPK activity. Levels of SKI messenger RNA (mRNA) encoding a TGF-β antagonist are sufficient to identify these patients. However, MDS patients with high SKI mRNA and chronic TGF-β signaling lack SKI protein because of miR-21 activity. To determine the impact of SKI loss, we examined murine Ski –/– HSC function. First, competitive HSC transplants revealed a profound defect in stem cell fitness (competitive disadvantage) but not specification, homing, or multilineage production. Aged recipients of Ski –/– HSCs exhibited mild phenotypes similar to phenotypes in those with macrocytic anemia. Second, blastocyst complementation revealed a dramatic block in Ski –/– hematopoiesis in the absence of transplantation. Similar to SKI- high MDS patient samples, Ski –/– HSCs strikingly upregulated TGF-β signaling and deregulated expression of spliceosome genes (including Hnrnpk ). Moreover, novel single-cell splicing analyses demonstrated that Ski –/– HSCs and high levels of SKI expression in MDS patient samples share abnormal alternative splicing of common genes (including those that encode splicing factors). We conclude that miR-21–mediated loss of SKI activates TGF-β signaling and alternative splicing to impair the competitive advantage of normal HSCs (fitness), which could contribute to selection of early-stage MDS-genic clones.
Muench, D. E., Ferchen, K., Velu, C. S., Pradhan, K., Chetal, K., Chen, X., Weirauch, M. T., Colmenares, C., Verma, A., Salomonis, N., Grimes, H. L.
American Society of Hematology (ASH)
0006-4971
00064971
1528-0020
15280020
shingle_catch_all_2 SKI controls MDS-associated chronic TGF-{beta} signaling, aberrant splicing, and stem cell fitness
Myeloid Neoplasia, e-Blood
The transforming growth factor beta (TGF-β) signaling pathway controls hematopoietic stem cell (HSC) behavior in the marrow niche; however, TGF-β signaling becomes chronic in early-stage myelodysplastic syndrome (MDS). Although TGF-β signaling normally induces negative feedback, in early-stage MDS, high levels of microRNA-21 (miR-21) contribute to chronic TGF-β signaling. We found that a TGF-β signal–correlated gene signature is sufficient to identify an MDS patient population with abnormal RNA splicing (eg, CSF3R ) independent of splicing factor mutations and coincident with low HNRNPK activity. Levels of SKI messenger RNA (mRNA) encoding a TGF-β antagonist are sufficient to identify these patients. However, MDS patients with high SKI mRNA and chronic TGF-β signaling lack SKI protein because of miR-21 activity. To determine the impact of SKI loss, we examined murine Ski –/– HSC function. First, competitive HSC transplants revealed a profound defect in stem cell fitness (competitive disadvantage) but not specification, homing, or multilineage production. Aged recipients of Ski –/– HSCs exhibited mild phenotypes similar to phenotypes in those with macrocytic anemia. Second, blastocyst complementation revealed a dramatic block in Ski –/– hematopoiesis in the absence of transplantation. Similar to SKI- high MDS patient samples, Ski –/– HSCs strikingly upregulated TGF-β signaling and deregulated expression of spliceosome genes (including Hnrnpk ). Moreover, novel single-cell splicing analyses demonstrated that Ski –/– HSCs and high levels of SKI expression in MDS patient samples share abnormal alternative splicing of common genes (including those that encode splicing factors). We conclude that miR-21–mediated loss of SKI activates TGF-β signaling and alternative splicing to impair the competitive advantage of normal HSCs (fitness), which could contribute to selection of early-stage MDS-genic clones.
Muench, D. E., Ferchen, K., Velu, C. S., Pradhan, K., Chetal, K., Chen, X., Weirauch, M. T., Colmenares, C., Verma, A., Salomonis, N., Grimes, H. L.
American Society of Hematology (ASH)
0006-4971
00064971
1528-0020
15280020
shingle_catch_all_3 SKI controls MDS-associated chronic TGF-{beta} signaling, aberrant splicing, and stem cell fitness
Myeloid Neoplasia, e-Blood
The transforming growth factor beta (TGF-β) signaling pathway controls hematopoietic stem cell (HSC) behavior in the marrow niche; however, TGF-β signaling becomes chronic in early-stage myelodysplastic syndrome (MDS). Although TGF-β signaling normally induces negative feedback, in early-stage MDS, high levels of microRNA-21 (miR-21) contribute to chronic TGF-β signaling. We found that a TGF-β signal–correlated gene signature is sufficient to identify an MDS patient population with abnormal RNA splicing (eg, CSF3R ) independent of splicing factor mutations and coincident with low HNRNPK activity. Levels of SKI messenger RNA (mRNA) encoding a TGF-β antagonist are sufficient to identify these patients. However, MDS patients with high SKI mRNA and chronic TGF-β signaling lack SKI protein because of miR-21 activity. To determine the impact of SKI loss, we examined murine Ski –/– HSC function. First, competitive HSC transplants revealed a profound defect in stem cell fitness (competitive disadvantage) but not specification, homing, or multilineage production. Aged recipients of Ski –/– HSCs exhibited mild phenotypes similar to phenotypes in those with macrocytic anemia. Second, blastocyst complementation revealed a dramatic block in Ski –/– hematopoiesis in the absence of transplantation. Similar to SKI- high MDS patient samples, Ski –/– HSCs strikingly upregulated TGF-β signaling and deregulated expression of spliceosome genes (including Hnrnpk ). Moreover, novel single-cell splicing analyses demonstrated that Ski –/– HSCs and high levels of SKI expression in MDS patient samples share abnormal alternative splicing of common genes (including those that encode splicing factors). We conclude that miR-21–mediated loss of SKI activates TGF-β signaling and alternative splicing to impair the competitive advantage of normal HSCs (fitness), which could contribute to selection of early-stage MDS-genic clones.
Muench, D. E., Ferchen, K., Velu, C. S., Pradhan, K., Chetal, K., Chen, X., Weirauch, M. T., Colmenares, C., Verma, A., Salomonis, N., Grimes, H. L.
American Society of Hematology (ASH)
0006-4971
00064971
1528-0020
15280020
shingle_catch_all_4 SKI controls MDS-associated chronic TGF-{beta} signaling, aberrant splicing, and stem cell fitness
Myeloid Neoplasia, e-Blood
The transforming growth factor beta (TGF-β) signaling pathway controls hematopoietic stem cell (HSC) behavior in the marrow niche; however, TGF-β signaling becomes chronic in early-stage myelodysplastic syndrome (MDS). Although TGF-β signaling normally induces negative feedback, in early-stage MDS, high levels of microRNA-21 (miR-21) contribute to chronic TGF-β signaling. We found that a TGF-β signal–correlated gene signature is sufficient to identify an MDS patient population with abnormal RNA splicing (eg, CSF3R ) independent of splicing factor mutations and coincident with low HNRNPK activity. Levels of SKI messenger RNA (mRNA) encoding a TGF-β antagonist are sufficient to identify these patients. However, MDS patients with high SKI mRNA and chronic TGF-β signaling lack SKI protein because of miR-21 activity. To determine the impact of SKI loss, we examined murine Ski –/– HSC function. First, competitive HSC transplants revealed a profound defect in stem cell fitness (competitive disadvantage) but not specification, homing, or multilineage production. Aged recipients of Ski –/– HSCs exhibited mild phenotypes similar to phenotypes in those with macrocytic anemia. Second, blastocyst complementation revealed a dramatic block in Ski –/– hematopoiesis in the absence of transplantation. Similar to SKI- high MDS patient samples, Ski –/– HSCs strikingly upregulated TGF-β signaling and deregulated expression of spliceosome genes (including Hnrnpk ). Moreover, novel single-cell splicing analyses demonstrated that Ski –/– HSCs and high levels of SKI expression in MDS patient samples share abnormal alternative splicing of common genes (including those that encode splicing factors). We conclude that miR-21–mediated loss of SKI activates TGF-β signaling and alternative splicing to impair the competitive advantage of normal HSCs (fitness), which could contribute to selection of early-stage MDS-genic clones.
Muench, D. E., Ferchen, K., Velu, C. S., Pradhan, K., Chetal, K., Chen, X., Weirauch, M. T., Colmenares, C., Verma, A., Salomonis, N., Grimes, H. L.
American Society of Hematology (ASH)
0006-4971
00064971
1528-0020
15280020
shingle_title_1 SKI controls MDS-associated chronic TGF-{beta} signaling, aberrant splicing, and stem cell fitness
shingle_title_2 SKI controls MDS-associated chronic TGF-{beta} signaling, aberrant splicing, and stem cell fitness
shingle_title_3 SKI controls MDS-associated chronic TGF-{beta} signaling, aberrant splicing, and stem cell fitness
shingle_title_4 SKI controls MDS-associated chronic TGF-{beta} signaling, aberrant splicing, and stem cell fitness
timestamp 2025-06-30T23:37:27.176Z
titel SKI controls MDS-associated chronic TGF-{beta} signaling, aberrant splicing, and stem cell fitness
titel_suche SKI controls MDS-associated chronic TGF-{beta} signaling, aberrant splicing, and stem cell fitness
topic W
WW-YZ
uid ipn_articles_6360033